Spinal muscular atrophy is an autosomal recessive neuromuscular disorder that is caused by an insufficient level of survival motor neuron (SMN) protein. Nusinersen is an antisense oligonucleotide ...drug that modifies pre-messenger RNA splicing of the SMN2 gene and thus promotes increased production of full-length SMN protein.
We conducted a randomized, double-blind, sham-controlled, phase 3 efficacy and safety trial of nusinersen in infants with spinal muscular atrophy. The primary end points were a motor-milestone response (defined according to results on the Hammersmith Infant Neurological Examination) and event-free survival (time to death or the use of permanent assisted ventilation). Secondary end points included overall survival and subgroup analyses of event-free survival according to disease duration at screening. Only the first primary end point was tested in a prespecified interim analysis. To control the overall type I error rate at 0.05, a hierarchical testing strategy was used for the second primary end point and the secondary end points in the final analysis.
In the interim analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (21 of 51 infants 41% vs. 0 of 27 0%, P<0.001), and this result prompted early termination of the trial. In the final analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (37 of 73 infants 51% vs. 0 of 37 0%), and the likelihood of event-free survival was higher in the nusinersen group than in the control group (hazard ratio for death or the use of permanent assisted ventilation, 0.53; P=0.005). The likelihood of overall survival was higher in the nusinersen group than in the control group (hazard ratio for death, 0.37; P=0.004), and infants with a shorter disease duration at screening were more likely than those with a longer disease duration to benefit from nusinersen. The incidence and severity of adverse events were similar in the two groups.
Among infants with spinal muscular atrophy, those who received nusinersen were more likely to be alive and have improvements in motor function than those in the control group. Early treatment may be necessary to maximize the benefit of the drug. (Funded by Biogen and Ionis Pharmaceuticals; ENDEAR ClinicalTrials.gov number, NCT02193074 .).
Background and Purpose
Cannabidiol has been reported to act as an antagonist at cannabinoid CB1 receptors. We hypothesized that cannabidiol would inhibit cannabinoid agonist activity through negative ...allosteric modulation of CB1 receptors.
Experimental Approach
Internalization of CB1 receptors, arrestin2 recruitment, and PLCβ3 and ERK1/2 phosphorylation, were quantified in HEK 293A cells heterologously expressing CB1 receptors and in the STHdhQ7/Q7 cell model of striatal neurons endogenously expressing CB1 receptors. Cells were treated with 2‐arachidonylglycerol or Δ9‐tetrahydrocannabinol alone and in combination with different concentrations of cannabidiol.
Key Results
Cannabidiol reduced the efficacy and potency of 2‐arachidonylglycerol and Δ9‐tetrahydrocannabinol on PLCβ3‐ and ERK1/2‐dependent signalling in cells heterologously (HEK 293A) or endogenously (STHdhQ7/Q7) expressing CB1 receptors. By reducing arrestin2 recruitment to CB1 receptors, cannabidiol treatment prevented internalization of these receptors. The allosteric activity of cannabidiol depended upon polar residues being present at positions 98 and 107 in the extracellular amino terminus of the CB1 receptor.
Conclusions and Implications
Cannabidiol behaved as a non‐competitive negative allosteric modulator of CB1 receptors. Allosteric modulation, in conjunction with effects not mediated by CB1 receptors, may explain the in vivo effects of cannabidiol. Allosteric modulators of CB1 receptors have the potential to treat CNS and peripheral disorders while avoiding the adverse effects associated with orthosteric agonism or antagonism of these receptors.
Classically regarded as motor structures, the basal ganglia subserve a wide range of functions, including motor, cognitive, motivational, and emotional processes. Consistent with this broad-reaching ...involvement in brain function, basal ganglia dysfunction has been implicated in numerous neurological and psychiatric disorders. Despite recent advances in human neuroimaging, models of basal ganglia circuitry continue to rely primarily upon inference from animal studies. Here, we provide a comprehensive functional connectivity analysis of basal ganglia circuitry in humans through a functional magnetic resonance imaging examination during rest. Voxelwise regression analyses substantiated the hypothesized motor, cognitive, and affective divisions among striatal subregions, and provided in vivo evidence of a functional organization consistent with parallel and integrative loop models described in animals. Our findings also revealed subtler distinctions within striatal subregions not previously appreciated by task-based imaging approaches. For instance, the inferior ventral striatum is functionally connected with medial portions of orbitofrontal cortex, whereas a more superior ventral striatal seed is associated with medial and lateral portions. The ability to map multiple distinct striatal circuits in a single study in humans, as opposed to relying on meta-analyses of multiple studies, is a principal strength of resting state functional magnetic resonance imaging. This approach holds promise for studying basal ganglia dysfunction in clinical disorders.
Climate change and land‐use change are widely altering freshwater ecosystem functioning and there is an urgent need to understand how these broad stressor categories may interact in future. While ...much research has focused on mean temperature increases, climate change also involves increasing variability of both water temperature and flow regimes and increasing concentrations of atmospheric CO2, all with potential to alter stream invertebrate communities. Deposited fine sediment is a pervasive land‐use stressor with widespread impacts on stream invertebrates. Sedimentation may be managed at the catchment scale; thus, uncovering interactions with these three key climate stressors may assist mitigation of future threats. This is the first experiment to investigate the individual and combined effects of enriched CO2, heatwaves, flow velocity variability, and fine sediment on realistic stream invertebrate communities. Using 128 mesocosms simulating small stony‐bottomed streams in a 7‐week experiment, we manipulated dissolved CO2 (ambient; enriched), fine sediment (no sediment; 300 g dry sediment), temperature (ambient; two 7‐day heatwaves), and flow velocity (constant; variable). All treatments changed community composition. CO2 enrichment reduced abundances of Orthocladiinae and Chironominae and increased Copepoda abundance. Variable flow velocity had only positive effects on invertebrate abundances (7 of 13 common taxa and total abundance), in contrast to previous experiments showing negative impacts of reduced velocity. CO2 was implicated in most stressor interactions found, with CO2 × sediment interactions being most common. Communities forming under enriched CO2 conditions in sediment‐impacted mesocosms had ~20% fewer total invertebrates than those with either treatment alone. Copepoda abundances doubled in CO2‐enriched mesocosms without sediment, whereas no CO2 effect occurred in mesocosms with sediment. Our findings provide new insights into potential future impacts of climate change and land use in running freshwaters, in particular highlighting the potential for elevated CO2 to interact with fine sediment deposition in unpredictable ways.
Climate change and human land use are two large threats to invertebrate communities in freshwaters, which are crucial to healthy ecosystems. We ran an experiment in stream mesocosms (small model systems), looking at the individual and interactive effects of heatwaves, carbon dioxide, variability in flow velocity, and fine sediment (related to agriculture). We found changes in community composition from all four, and several interactions involving CO2 and sediment. Our results, although limited, provide insight into potential effects of some poorly understood climate variables and suggest certain CO2 effects in streams may be strongly influenced by sediment.
Increased intraindividual variability (IIV) is a hallmark of disorders of attention. Recent work has linked these disorders to abnormalities in a “default mode” network, comprising brain regions ...routinely deactivated during goal-directed cognitive tasks. Findings from a study of the neural basis of attentional lapses suggest that a competitive relationship between the “task-negative” default mode network and regions of a “task-positive” attentional network is a potential locus of dysfunction in individuals with increased IIV. Resting state studies have shown that this competitive relationship is intrinsically represented in the brain, in the form of a negative correlation or antiphase relationship between spontaneous activity occurring in the two networks. We quantified the negative correlation between these two networks in 26 subjects, during active (Eriksen flanker task) and resting state scans. We hypothesized that the strength of the negative correlation is an index of the degree of regulation of activity in the default mode and task-positive networks and would be positively related to consistent behavioral performance. We found that the strength of the correlation between the two networks varies across individuals. These individual differences appear to be behaviorally relevant, as interindividual variation in the strength of the correlation was significantly related to individual differences in response time variability: the stronger the negative correlation (i.e., the closer to 180° antiphase), the less variable the behavioral performance. This relationship was moderately consistent across resting and task conditions, suggesting that the measure indexes moderately stable individual differences in the integrity of functional brain networks. We discuss the implications of these findings for our understanding of the behavioral significance of spontaneous brain activity, in both healthy and clinical populations.
The edge-to-edge matching model for describing the interfacial crystallographic characteristics between two phases that are related by reproducible orientation relationships has been applied to the ...typical grain refiners in aluminum alloys. Excellent atomic matching between Al
3Ti nucleating substrates, known to be effective nucleation sites for primary Al, and the Al matrix in both close packed directions and close packed planes containing these directions have been identified. The crystallographic features of the grain refiner and the Al matrix are very consistent with the edge-to-edge matching model. For three other typical grain refiners for Al alloys, TiC (when
a
=
0.4328 nm), TiB
2 and AlB
2, the matching only occurs between the close packed directions in both phases and between the second close packed plane of the Al matrix and the second close packed plane of the refiners. According to the model, it is predicted that Al
3Ti is a more powerful nucleating substrate for Al alloy than TiC, TiB
2 and AlB
2. This agrees with the previous experimental results. The present work shows that the edge-to-edge matching model has the potential to be a powerful tool in discovering new and more powerful grain refiners for Al alloys.
Abstract The McGill consensus statement on overdentures (14) was published following a symposium held at McGill University in Montreal, Canada in 2002. A panel of relevant experts in the field stated ...that: The evidence currently available suggests that the restoration of the edentulous mandible with a conventional denture is no longer the most appropriate first choice prosthodontic treatment. There is now overwhelming evidence that a two-implant overdenture should become the first choice of treatment for the edentulous mandible (14). In 2009, a further consensus statement was released as a support and follow-up to the McGill consensus statement. This report was jointly created by members of the BSSPD (British Society for the Study of Prosthetic Dentistry) Council and the panel of presenters at the BSSPD conference in York, UK in April 2009 (15). This report also highlighted that since the McGill statement in 2002, uptake by dentists of implant technology for complete denture wearers has been slow. The York statement concluded that ‘a substantial body of evidence is now available demonstrating that patients’ satisfaction and quality of life with ISOD mandibular overdentures is significantly greater than for conventional dentures. Much of this data comes from randomised controlled trials (15). Whilst it is accepted that the two-implant overdenture is not the gold standard of implant therapy it is the minimum standard that should be sufficient for most people, taking into account performance, patient satisfaction, cost and clinical time.
Human cerebral development is remarkably protracted. Although microstructural processes of neuronal maturation remain accessible only to morphometric post-mortem studies, neuroimaging tools permit ...the examination of macrostructural aspects of brain development. The analysis of resting-state functional connectivity (FC) offers novel possibilities for the investigation of cerebral development. Using seed-based FC methods, we examined the development of 5 functionally distinct cingulate-based intrinsic connectivity networks (ICNs) in children (n = 14, 10.6 ± 1.5 years), adolescents (n = 12, 15.4 ± 1.2) and young adults (n=14, 22.4 ± 1.2). Children demonstrated a more diffuse pattern of correlation with voxels proximal to the seed region of interest (ROI) (“local FC”), whereas adults exhibited more focal patterns of FC, as well as a greater number of significantly correlated voxels at long distances from the seed ROI. Adolescents exhibited intermediate patterns of FC. Consistent with evidence for different maturational time courses, ICNs associated with social and emotional functions exhibited the greatest developmental effects. Our findings demonstrate the utility of FC for the study of developing functional organization. Moreover, given that ICNs are thought to have an anatomical basis in neuronal connectivity, measures of FC may provide a quantitative index of brain maturation in healthy subjects and those with neurodevelopmental disorders.
Abstract
The GLASS-JWST Early Release Science (hereafter GLASS-JWST-ERS) Program will obtain and make publicly available the deepest extragalactic data of the ERS campaign. It is primarily designed ...to address two key science questions, namely, “what sources ionized the universe and when?” and “how do baryons cycle through galaxies?”, while also enabling a broad variety of first look scientific investigations. In primary mode, it will obtain NIRISS and NIRSpec spectroscopy of galaxies lensed by the foreground Hubble Frontier Field cluster, Abell 2744. In parallel, it will use NIRCam to observe two fields that are offset from the cluster center, where lensing magnification is negligible, and which can thus be effectively considered blank fields. In order to prepare the community for access to this unprecedented data, we describe the scientific rationale, the survey design (including target selection and observational setups), and present pre-commissioning estimates of the expected sensitivity. In addition, we describe the planned public releases of high-level data products, for use by the wider astronomical community.
A systematic review of studies in humans was conducted to update evidence on the association between the amount of sugars intake and dental caries and on the effect of restricting sugars intake to < ...10% and < 5% energy (E) on caries to inform the updating of World Health Organization guidelines on sugars consumption. Data sources included MEDLINE, EMBASE, Cochrane Database, Cochrane Central Register of Controlled Trials, Latin American and Caribbean Health Sciences, China National Knowledge Infrastructure, Wanfang, and South African Department of Health. Eligible studies reported the absolute amount of sugars and dental caries, measured as prevalence, incidence, or severity. The review was conducted and reported in accordance with the PRISMA statement, and the evidence was assessed according to GRADE Working Group guidelines. From 5,990 papers identified, 55 studies were eligible – 3 intervention, 8 cohort, 20 population, and 24 cross-sectional. Data variability limited meta-analysis. Of the studies, 42 out of 50 of those in children and 5 out of 5 in adults reported at least one positive association between sugars and caries. There is evidence of moderate quality showing that caries is lower when free-sugars intake is < 10% E. With the < 5% E cut-off, a significant relationship was observed, but the evidence was judged to be of very low quality. The findings are relevant to minimizing caries risk throughout the life course.
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